Ephedrine-aldehyde compound and solution and process of preparing such compound



-\ hyde, heptaldehyde,

aldehyde,

i benzaldehyde,

Patented use 4,1930

(UNITED STATES P ATENr-" H ELHEB H. STUART, OF INDIANAPOLIS, INDIANA ASSIGNOR TO ELI LILLY AND COM- Pm, OF INDIANAPOLISQ IHDIANA, A CORPORATION OF INDIANA mmmunms courounn AND summon ANDPROCESS or rnnmnme soon conrotmn Ho Drawing.

My present invention relates to certain new chemical compounds, involving the combination of an ephedrine with aldehydes, to oil solutions of such compounds, and to the 5 process of preparing such compounds.

These new compounds'hav'e certain advantages in connection with the use of ephedrine, especially in certain ph siological treatments; as they appear to loless irritating than the alkaloid ephedrine it'- self, in many instances are oil-soluble or at least more oilesoluble than the alkaloid .ephedrine itself, in most instances are substanr tially equally physiologically active.

y In using the term an ephedrine, I have in mind not only the levo-rotatory ephedrine which is now most commonly known by that name, but also the various isomeric forms of ephedrine of the general formula:

a 10 0a a; w l

of an ephedrine with aldehydes. or instance, I have combined an ephedrine with formaldehyde, acetaldehyde, phen lacetaldeanisaldehy e,. furfur salicylaldehyde, 'vetratraldehyde, citral, vanillin, benzaldehyde, o-methoxytimes using ordinary l-ephedrine and'sometimes d-pseudoephed'rine. tions of the aldehydes with ordinary l-ephedrine, that are physiologically So far as I am aware,

aldehyde compounds are new with me with the exception of ephedrine-benzaldehyde and pseudoephedrine-benza1dehyde and my process o forming such compounds, and my oil solut ons of such compounds, arenew with me as to such-compounds Without ex ,ception.

The compounds of ephedrine and-pseudothe most active.

ephedrine with'benzaldehyde have been de v scribed, in a paper by Ernest Schmidt beginning. on page 89 of Archiv derPharmaz1e for1914. In that paper it is pointed out quite generally 7 even in the case where thealdehyde is enthe aldehyde component is benzaldehyde. 25 I have made a number of these; com ounds and cinnamic aldehyde; somep with definite physical properties, and in some The combina-' .able heat in the reaction.

which is levo-rotatory, are the ones,

all-these ephedrine- 'the aldehyde, in substantially the theoretical if the aldehyde is a-solid atordinary'temper- "ether solutionof Application meg lay a, 1928. serial No. 274,965.

that benzaldehyde is an oxidation-decomposition product of ephedrine and of pseudoephedrme, and that such benzaldehyde combines with ephedrine and with pseudoephedrme to form benzal-ephedrine and benzalpseudoephedrine respectively.

However, that article describes no compounds of. either ephedrine or pseudoephevdrine with any aldehyde save benzaldehyde;

which, as the paper points out, is an oxidation-decomposition product of ephedrine and' pseudoephedrine. Thus it is new with me, so far as I know, to rovide compounds of an ephedrine with an a dehyde which is not itself an oxidation-decomposition product of an ephedrine. Y

Neither does that article describe theproces 's which is set forth in the. present a lication of producing an ephedrine-a1 e 'de,

zaldehyde. Thus such process is new with me, so far as I know, for any ephedrine-aldehyde compound, including the compounds where instances with the development of considera Inproducing these compounds, I find it convenient to dissolve the desired amount of an, ephedrine in ether, and then to add amount for a 1-to-1 molecular combination, to the ether solution of the ephedrine. If the aldehyde is itself 1i uid, as in the case of acetaldehyde, it may e poured directly into the ether solution of the ephedrine; whereas atures, as in the case of vanillin, I may dissolve it separately in ether and then mix thethe aldehyde and the ether solution of the ephedrine.

The combination usually takes place at distillation to drive off most of the ether,

and then by vacuum evaporation over a water bath to remove the remaining ether.

During the last part of the evaporation of the ether, the water which is formed by the reaction is usually noticed as separate from the ephedrine-aldehyde compound produced;

and this water may be removed by the last part of the vacuum evaporation.

The final results thus obtainedhave definite physical properties.

The compound of d-pseudo-ephedrine and formaldehyde is a liquid at ordinary temperatures, with a slight yellow color.

The compound of ordinary l-ephedrine with acetaldehyde is a v liquid at ordinary temperatures, having a slight yellow color, with a boiling point'of 23 9 0. Its refractive index at 25 C. is 1.5112. This compound of acetaldehyde with ordinary l-ephedrine appears to be rather unstable, as in the course of several weeks it develops a somewhat different odor. its original odor being something like that of acetaldehyde, and the odor later being something. like that of phosphorus.

An assa-y of the fresh compound of ordinary l-ephedrine and acetaldehyde shows it to contain the equivalent of 85% of its weight of the original alkaloid; which is fairly close to the theoretical value of 86.4% in a combination in the proportion of one molecule of ephedrine to one molecule of acetaldehyde with the elimination of one molecule of water.

The compound of ordinary l-ephedrine with furfur aldehyde is a solid at ordinary temperatures. Its melting point is 48 C. It appears to be unstable, as its odor changes on standing.

The compound of ordinary l-ephedrine with citral is a liquid at ordinary temperatures. that of light parafiin oil.

The compound of ordinary .lephedrine with heptaldehyde is a colorless liquid at ordinary temperatures. In absolute alcohol at 25 0., it hasan optical rotation of 4:2.8.

- The compound of ordinary 'l-ephedrine with benzaldehyde is a white crystalline solid :at ordinary temperatures. Its melting int is 73 C. It can be purified by recrysta lization from 95% alcohol. In absolute alcohol at 25 0., it has an optical rotation of 531. This compound is described in the aforesaid Schmidt paper, but my method of preparing it is not there described.

The: compound of ordinary l-ephedrine with anisaldehyde is a white crystalline powder. It can be urified by recrystallization from.95% alco 01. Its melting point is It has a viscosity comparable with 895 C. Its'optical rotation when dissolved in absolute alcohol at 25 C. is -54.4.

The compound of ordinary l-ephedrine with o-methoxy-benzaldehyde is a white crystalline powder. Its melting point is 103.5 C. It can be purified by'recrystallization from absolute alcohol.

The compound of ordinary l-ephedrine with salicylaldehyde is a white crystalline powder. Its melting point is 117 C. It can be purified by recrystallization from absolute alcohol.

The compound of l-ephedrine with vitratraldehyde is a white crystalline powder when recrystallized from absolute alcohol. Its melting point is 97 C. u The compound of ordinary l-ephedrine with vanillin is a resin-like solid at ordinary temperatures, having initially a slight yellow color that changes" to a yellowish red upon standing. Its melting point is not definite. This compound of ordinary l-ephedrine with vanillin appears not to be entirely stable, as evidenced by the change in color above noted.

The compound of ordinary l-ephedrine with cinnamic aldehyde is a solid at ordinary namic' aldehyde shows it to contain the equivalent of 58.9% of its weight of thejoriginal alkaloid; whereas theoretically the combination in the proportion of one molecule of ephedrine to one molecule of cinnamic aldehyde, less; one molecule of'water, is 59.14% of alkaold.

I have hydrolyzed the compound of cin namic aldehyde and l-ephedrine by means of acid alcohol, and re-obtained the original ordinary l-ephedrine unchanged.

The compound of d-pseudo-ephedrine with cinnamic aldehyde is a white crystalline powder, which can be purified by re-crystallization from absolute alcohol. It has a melting point of 75 C. When dissolved in absolute alcohol at 25 C., it has an optical rotation of 329.

The compound of d-pseudo-ephedrine and benzaldehyde is a solid at ordinary temperature's, with a meltingpoint of 67 C. An 'assay shows an equivalent of 64.48% d-pseudoephedrine. This compound is described in the aforesaid Schmidt paper, but my method of preparing it is not there described.

The compound of salicylaldehyde with dpseudo-ephedrine is a solid atordinary temperatures, with a melting point of about 79 to 80 Cf The compound of d-pseudo-ephedrine and w molecular proportion.

vanillin is a solid at ordinary temperatures, with a melting point of about 124.5 to 125 C.

The foregoing are merely a few examples of a number of compounds of this nature which may be produced.

The physical properties given above for the various compounds may be found to vary slightly upon further purification. For instance, the compounds which are described as having a slight yellow color may be found on further purification to be white.

Most of these compounds are oilsoluble to a greater or less extent. The compounds of ordinary l-ephedrine with acetaldehyde, citral. heptaldehyde, and cinnamic aldehyde are soluble in paraflin oil as a menstruum to at least 2% or more, at a temperature of 15 C. or higher, and when so dissolved the resultant oil solutions are found to be suitable as oil-ephedrine inhalants or nasal sprays; while theother compounds mentioned are in general less soluble than those four. Those which are less soluble can nevertheless be dissolved in paraffin oil if certain other substances are added; as for instance ethyl alcohol or isopropylalcohol, or some additional ephedrine over that necessary for the -1--1 The fairly ready oil solubility of these compounds of an ephedrine with aldehydes makes them readily available for use .in oil, as for application in the nose. Most of these oil solutions when used as nasal sprays or inhalants are substantially non-irritating to the mocous membranes, and all of them are apparently less irritatingthan is the oil solution of the alkaloid ephedrine itself.

In addition to the aldehyde-ephedrine compounds which am oil-soluble to a greater or less extent, there are some such compounds which are oil-insoluble.

The compound of ordinary l-e'phedrine with protocatechuic aldehyde is a red-brown resin-like solid at ordinary temperatures; and is practically insoluble in parafiin oil.

The compound of ordinary l-ephedrine with p-hydroxy-benzaldehyde is a bloodred resin-like solid at ordinarytemperatures; and is'practically insoluble 'in paraffin oil.

All of these compounds, both those which are oil soluble and those -which are oil-insoluble, are soluble in alcohol.

I claim as my invention:

1. A compound obtained by the reaction of 1 molof l-ephedrine with 1 mol of an aldehyde other decomposition product of such ephedrine.

2. A compound obtained by the reaction'of '1 mol of an ephedrine with 1 mol of an aldehyde other than one which is an oxidationdecomposition product of such ephedrine, with the elimination-of 1 mol ofwater.

3. A compound which is produced by the re-action of an ephedrine with an aldehyde other than one ,which is an oxidation-decom- 'between an ephedrine and consists in bringing them together in a solvent than one which'is an oxidation position product of such ephedrine, with the elimination of water. I

4. The process of producing a compound an aldehyde, which in which both the ephedrine and aldehyde are freely soluble.

5. The process of formin an ephedrine with an aldehy e, which consists in dissolving the ephedrine in ether, and addingto the resultant solution an ether solution of an aldehyde.

6. The process of forming a compound of an ephedrine with an aldehyde, which consists in dissolving the ephedrine in ether, and

a compound of adding to the resultant solution an aldehyde.

7 The process of forming a compound of an ephedrine with an aldehyde, which consists in dissolving the ephedrine in a solvent which is capable of dissolving both the ephedrine and aldehyde, and adding to the re sultantsolution a solution of in the same solvent.

8. A compound which is produced by the re-action of l-ephedrine with an aldehyde other than one which is an oxidation-decomposition productof such ephedrine.

9. A nasal spray, consisting in oil as a menstruum, and a compound dissolved therein that is obtained by the reaction of one mol of l-ephedrine with one mol of an aldehydel 10. A nasal spray, consisting in oil as a ngenstruum, and a compound dissolved therei that is obtained by the reaction of one mol of an ephedrine with one mol of an'aldehyde.

11. A nasal spray, consisting in oil as a menstruum, and a compound dissolved therethe aldehyde in 'that is produced by the reaction of hand at Indianapolis, Indiana, this 1st day of May, A. D. one thousand nine hundred and twenty-eight.

' ELMER .H. STUART. 

